Cancer-related inflammation can fall into one of two categories: 1. precancerous inflammation lesions and 2. Inflammation that is present in almost all cancer tissues including those that have no precancerous inflammation lesions. The connection between inflammation and cancer can be thought of as consisting of two pathways: an extrinsic mechanism, where a constant inflammatory state contributes to increased cancer risk (such as inflammatory bowel disease); and an intrinsic mechanism, where acquired genetic alterations (such as activation of oncogenes) trigger tumor development (see figure, Inflammation of external origin is responsible for increased cancer risk via induction of genetic and epigenetic aberrations in affected cells).

The former can increase the risk to cancer development, while the latter are necessary to maintain and promote cancer progression. The roles and the relationship between the two pathways in the cancer development process depend on their specific interactions between genetic/epigenetic factors and environmental factors. The accumulated evidence, obtained using in vivo and in vitro genetic disease models and the analysis of clinical patient samples by various methods including PCR analysis, strongly favors the theory that both precancerous inflammation and inflammation stemming from genetic alteration can cause cell transformation and promote tumor progression. There is strong evidence that inflammation contributes to the incidence of and mortality resulting from a number of tumor types. Examining this relationship via real-time PCR analysis of gene expression and epigenetic state in the inflammatory and tumor microenvironment will contribute to our understanding of cancer initiation and progression and will aid in the discovery of biomarkers for clinical use and drug development (1-3).

Inflammation is present in cancer tissues that arose without precancerous inflammation. The inflammatory state is necessary to maintain and promote cancer progression and accomplish the full malignant phenotype, such as tumor tissue remodeling, angiogenesis, metastasis and the suppression of the innate anticancer immune response (6). In these cancers, inflammation is elicited by genetic and/or epigenetic mutation that triggers cell transformation and maintains the autonomous proliferation of the transformed cells.

Tumor-infiltrating leucocytes as well as cytokine related signaling pathways are critical components in the development of the inflammatory tumor microenvironment. Understanding the roles of each type of cell and signaling pathway involved in cancer initiation and progression is critical to the discovery of biomarkers specifically targeting cancer inflammation (7-9).

Back to top "Smoldering" inflammation can increase the cancer risk by accumulating genetic and epigenetic damage

Increased cancer risk is attributed to the observation that chronic inflammation can cause genetic damage via production of oxidizing compounds, such as reactive oxygen and nitrogen species. These products can induce the formation and accumulation of mutagenic, toxic, and/or genome-destabilizing DNA lesions (1, 10-15) . Inflammation related signaling has also been shown to suppress the activity of the DNA damage repair system (1). For example, neutrophils, the major source of reactive oxygen species, can also inhibit DNA base-excision repair (16, 17). IL-10, an important anti-inflammatory cytokine, can suppress the activity of the DNA damage response. In IL-10 knock out mice, a genetic mouse model of inflammatory bowel disease, the frequency of DNA mutations in colon tissue, in the absence of exogenous carcinogen, is 4-5 times higher than in wild type mice (18).

Epigenetic damage, such as aberrant DNA methylation, aberrant histone modification and miRNA expression is well recognized as a major driving force in cancer development and progression (19, 20). The presence of reactive oxygen species in the inflammatory state has been associated with epigenetic damage (21). Reactive oxygen species can induce aberrant DNA methylation via DNA damage. This is believed to be the mechanism of chemical or radiation associated aberrant DNA methylation.

Polycomb complex target genes (PcGs) play an important role in embryonic development and aging via epigenetic reprogramming. These genes are the major targets of aberrant DNA methylation and histone modification in cancer cells. In a mouse model of intestinal inflammation and cancer, not only is inflammation associated with increased global aberrant DNA methylation, but more than 70% of aberrantly methylated genes were PcGs (22).

Helicobacter pylori infection is a well characterized example of increased cancer risk in the setting of bacterial infection. Inflammation caused by bacterial infection has been shown to markedly increase cancer risk. This has been correlated with aberrant DNA methylation in gastric epithelial cells (23).

To obtain a malignant phenotype, the cell needs to acquire genetic or epigenetic mutations to trigger transformation. This malignant phenotype must then be maintained. The inflammatory response in cancer tissues play an important role in maintaining the phenotype by inducing tumor tissue remodeling, angiogenesis, and metastasis; all while suppressing the innate anticancer immune response (6). Such an inflammatory response can be elicited by activated oncogenic signaling pathways. This is well established in human papillary thyroid cancer. In human papillary thyroid carcinoma, activation of the RET oncogene by chromosome rearrangement is sufficient to trigger transformation of a thyrocyte to a carcinoma (24). The activated RET oncogene can also activate a program of inflammatory genes in affected thyrocytes. Activated genes include colony-stimulating factors (CSFs), interleukin 1β (IL-1β), cyclooxygenase 2 (COX2), CC-chemokine ligand 2 (CCL2) and CCL20, IL-8 or CXC-chemokine ligand 8 (CXCL8 CXC-chemokine receptor 4 (CXCR4), extracellular-matrix-degrading enzymes, and lymphocyte selectin (L-selectin) (see figure, RET oncogenic signaling pathway activation is a well-characterized example for the intrinsic origin of cancer inflammation). RET-activated inflammatory proteins were found in tumor biopsies. Interestingly, larger amounts of these inflammatory molecules were found in primary tumors from patients with lymph-node metastasis than in primary tumors without lymph-node metastasis. This observation suggests that the higher activity of the inflammatory pathway is associated with thyroid carcinoma metastasis. The specific role of these factors in the development of the cancer phenotype are not yet clear.

The Ras-Raf signaling pathway has been shown to cooperate with chronic inflammation to facilitate cell transformation. In a mouse model, both chronic pancreatitis and mutated K-ras are required to induce pancreatic intra-epithelial neoplasia and invasive ductal carcinoma. While aberrant Ras-Raf signaling can drive tumor-promoting inflammation to a certain extent, an extrinsic inflammatory condition such as pancreatitis is needed to drive carcinogenesis (25).

The NFκB signaling pathway is a key coordinator of innate immunity and inflammation. NFκB signaling plays crucial roles in both precancerous chronic inflammation as well as cancer induced inflammation. Frequently activated by cancer gene mutation, NFκB is an important regulator of tumor initiation and progression. Activation of this pathway induces expression of inflammatory cytokines, adhesion molecules, enzymes in the prostaglandin-synthesis pathway (such as COX2), inducible nitric oxide synthase (iNOS) angiogenic factors and anti-apoptotic genes (such as Bcl-2) (3).

Unchecked activation of immune associated signaling pathways has been associated with the development and maintenance of the tumor phenotype. The Ras-Raf signaling pathway is frequently mutated and aberrantly activated in many human cancers. Activation of this pathway induces the expression of tumor promoting chemokines and cytokines (25). Myc oncogene activation has been associated with the remodeling of the extracellular microenvironment, a process requiring cytokines, chemokines, and recruited mast cells. This process promotes tumor angiogenesis and metastasis (17). Tumor suppressor genes PTEN, p16, p53 (1, 26) and VHL have also been implicated in the induction of inflammatory mediators that may contribute to tumor progression (27).

Similar to NFκB, the STAT3 - TGFβ signaling pathway is involved in numerous oncogenic signaling pathways (28, 29). These transcription factors are constitutively activated in tumor cells and are involved in oncogenesis and inhibition of apoptosis. The activation of STAT3 in tumor cells has also been implicated in immune evasion via inhibition of dendritic cell maturation and the subsequent immune response.

Despite the exciting advances in the field of cancer inflammation research, many questions remain. The cross talk between the different signaling pathways involved in cancer-related inflammation is an area that remains unclear. This is not surprising based on the high heterogeneity of genetic and epigenetic alterations present in different cancers, differences in host genetic background as well as tissue specific inflammatory responses. Many challenges lie ahead: Are there aspects of cancer-related inflammation common to all malignancies? Are there unique inflammation biomarkers that can discriminate cancer related inflammation from non-cancer related inflammation? What is the relationship between the components and mediators of the cancer inflammatory response? How can cancer-related inflammatory pathways be targeted for drug development? Defining the roles of inflammatory mediators and the underlying signaling pathways will be critical to increasing the understanding of cancer initiation and progression. This will aid in the discovery of biomarkers for disease stratification, molecular diagnosis & prognosis, therapy selection and drug development.